17-34983476-C-A

Position:

• chr17-34983476-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_013975.4(LIG3):​c.471C>A​(p.Ile157=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,020 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: LIG3 NM_013975.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.71

Genes affected

LIG3 (HGNC:6600): (DNA ligase 3) This gene is a member of the DNA ligase family. Each member of this family encodes a protein that catalyzes the joining of DNA ends but they each have a distinct role in DNA metabolism. The protein encoded by this gene is involved in excision repair and is located in both the mitochondria and nucleus, with translation initiation from the upstream start codon allowing for transport to the mitochondria and translation initiation from a downstream start codon allowing for transport to the nucleus. Additionally, alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 17-34983476-C-A is Benign according to our data. Variant chr17-34983476-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 632876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00131 (200/152200) while in subpopulation NFE AF= 0.00209 (142/68020). AF 95% confidence interval is 0.00181. There are 0 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG3	NM_013975.4	c.471C>A	p.Ile157=	synonymous_variant	2/20	ENST00000378526.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG3	ENST00000378526.9	c.471C>A	p.Ile157=	synonymous_variant	2/20	1	NM_013975.4	P1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 200 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00108 AC: 271 AN: 250154 Hom.: 3 AF XY: 0.00109 AC XY: 148 AN XY: 135706

Gnomad AFR exome AF: 0.000510

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00149 AC: 2179 AN: 1461820 Hom.: 2 Cov.: 34 AF XY: 0.00142 AC XY: 1035 AN XY: 727208

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000842

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74428

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000944

Gnomad4 NFE AF: 0.00209

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00121

EpiCase AF: 0.00191

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 15, 2018

Variant summary: The LIG3 c.471C>A (p.Ile157Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 317/276846 control chromosomes (3 homozygotes) at a frequency of 0.001145, which is approximately 115 times the estimated maximal expected allele frequency of a pathogenic LIG3 variant (0.00001), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.26
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61749869; hg19: chr17-33310495;